Strategies for improving IPAD

Agents that improve contractility of vascular smooth muscle cells

Phosphodiesterase III is the major cAMP-hydrolyzing PDE uniquely expressed in vascular smooth muscle cells; PDE IIIA isoforms are also involved in cardiovascular function by regulating vascular smooth muscle growth and phenotypic changes. Cilostazol is a selective inhibitor of PDE III that increases cAMP in vascular cells and has multiple effects on the vasculature such as vasodilatation, anti-oxidation, anti-inflammation, regulation of smooth muscle cells, increase in cerebral haemodynamics and arterial elasticity with maintenance of microvascular integrity, as reviewed in (19). Cognition is significantly improved in experimental models and in humans receiving Cilostazol (20)(21)(22)(23). Administration of Cilostazol significantly improves IPAD and the brains of mice treated with Cilostazol show effects upon extracellular matrix, with upregulation of the anti-fibrillogenic glycoproteins (24)(25).

Using chaperones for efficient transport along the IPAD pathways

Clusterin (Apolipoprotein J) is a multifunctional protein that reduces the aggregation and toxicity of Aβ and appears to be beneficial in atherosclerosis (26)(27)We recently demonstrated that in APP/PS1 mouse models of Alzheimer’s disease, crossed with clusterin knockout mice, result in disappearance of Aβ plaques but an increase in severity of CAA. These findings suggest that clusterin is required for efficient chaperoning of solubilized proteins from plaques along IPAD (28). Administration of clusterin as a preventative therapy when the integrity and function of smooth muscle cells and basement membranes are not compromised may yield positive results for the prevention or delay in onset of symptoms of CAA and Alzheimer’s disease. Taxifolin is flavonoid that appears to maintain amyloid in its soluble forms more amenable for clearance (29) We are investigating whether Taxifolin facilitates IPAD.

Agents acting upon the innervation of smooth muscle cells

Experimental work is ongoing in this area. Results suggest that agents such as Prazosin, an alpha(1)-adrenoceptor antagonist, acting upon cholinergic or adrenergic innervation of cerebral arteries result in improvements of IPAD and in reduction of CAA in transgenic mouse models of Alzheimer’s disease (30).

Current projects

Strategies for improving IPAD

Innervation of cerebral arteries is key for maintenance of IPAD

This project, funded by Alzheimer’s Research UK in collaboration with Dr Cheryl Hawkes (Open University), tests the hypothesis that loss of perivascular innervation by cholinergic neurons leads to dysfunctional regulation of vascular tone, thereby reducing the motive force for perivascular drainage of Aβ leading to a worsening of cerebral amyloid angiopathy. 

Key researcher

Maureen Gatherer

SENIOR RESEARCH TECHNICIAN

  • m.gatherer@soton.ac.uk

Output

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer's Disease. Frost, M, Keable, A, Baseley, D, Sealy, A, Andreea Zbarcea, D et al.. Pharmaceuticals (Basel). 2020;13 (9):. doi: 10.3390/ph13090261. PubMed PMID:32971843 PubMed Central PMC7560129.

Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia. MacGregor Sharp, M, Saito, S, Keable, A, Gatherer, M, Aldea, R et al.. Acta Neuropathol Commun. 2020;8 (1):131. doi: 10.1186/s40478-020-01009-1. PubMed PMID:32771063 PubMed Central PMC7414710.

ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes. Keable, A, O'Neill, R, MacGregor Sharp, M, Gatherer, M, Yuen, HM et al.. Int J Mol Sci. 2020;21 (12):. doi: 10.3390/ijms21124371. PubMed PMID:32575521 PubMed Central PMC7352194.

A lasered mouse model of retinal degeneration displays progressive outer retinal pathology providing insights into early geographic atrophy. Ibbett, P, Goverdhan, SV, Pipi, E, Chouhan, JK, Keeling, E et al.. Sci Rep. 2019;9 (1):7475. doi: 10.1038/s41598-019-43906-z. PubMed PMID:31097765 PubMed Central PMC6522499.

AAV2/8 Anti-angiogenic Gene Therapy Using Single-Chain Antibodies Inhibits Murine Choroidal Neovascularization. Hughes, CP, O'Flynn, NMJ, Gatherer, M, McClements, ME, Scott, JA et al.. Mol Ther Methods Clin Dev. 2019;13 :86-98. doi: 10.1016/j.omtm.2018.11.005. PubMed PMID:30719487 PubMed Central PMC6350388.

Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aβ Drainage. Diem, AK, MacGregor Sharp, M, Gatherer, M, Bressloff, NW, Carare, RO et al.. Front Neurosci. 2017;11 :475. doi: 10.3389/fnins.2017.00475. PubMed PMID:28883786 PubMed Central PMC5574214.

Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Wojtas, AM, Kang, SS, Olley, BM, Gatherer, M, Shinohara, M et al.. Proc Natl Acad Sci U S A. 2017;114 (33):E6962-E6971. doi: 10.1073/pnas.1701137114. PubMed PMID:28701379 PubMed Central PMC5565413.

Investigating the Lymphatic Drainage of the Brain: Essential Skills and Tools. Albargothy, NJ, Sharp, MM, Gatherer, M, Morris, A, Weller, RO et al.. Methods Mol Biol. 2017;1559 :343-365. doi: 10.1007/978-1-4939-6786-5_24. PubMed PMID:28063056 .

Systems proteomic analysis reveals that clusterin and tissue inhibitor of metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy. Manousopoulou, A, Gatherer, M, Smith, C, Nicoll, JAR, Woelk, CH et al.. Neuropathol Appl Neurobiol. 2017;43 (6):492-504. doi: 10.1111/nan.12342. PubMed PMID:27543695 PubMed Central PMC5638106.

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Hawkes, CA, Gatherer, M, Sharp, MM, Dorr, A, Yuen, HM et al.. Aging Cell. 2013;12 (2):224-36. doi: 10.1111/acel.12045. PubMed PMID:23413811 .

Rat astrocytic tumour cells are associated with an anti-inflammatory microglial phenotype in an organotypic model. Billingham, C, Powell, MR, Jenner, KA, Johnston, DA, Gatherer, M et al.. Neuropathol Appl Neurobiol. 2013;39 (3):243-55. doi: 10.1111/j.1365-2990.2012.01283.x. PubMed PMID:22631872 .

Aberrant Timm-stained fibres in the dentate gyrus following tetanus toxin-induced seizures in the rat. Mitchell, J, Gatherer, M, Sundstrom, LE. Neuropathol Appl Neurobiol. 1996;22 (2):129-35. . PubMed PMID:8732188 .

Hippocampal NPY neurons project to the fascia dentata in organotypic cultures. Mitchell, J, Gatherer, M, Best, N, Sundstrom, L, Wheal, HV et al.. Hippocampus. 1996;6 (2):173-82. doi: 10.1002/(SICI)1098-1063(1996)6:2<173::AID-HIPO7>3.0.CO;2-Q. PubMed PMID:8797017 .

Loss of hilar somatostatin neurons following tetanus toxin-induced seizures. Mitchell, J, Gatherer, M, Sundstrom, LE. Acta Neuropathol. 1995;89 (5):425-30. doi: 10.1007/BF00307647. PubMed PMID:7542423 .

Search PubMed

Output

Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice. Nizari, S, Wells, JA, Carare, RO, Romero, IA, Hawkes, CA et al.. Acta Neuropathol Commun. 2021;9 (1):12. doi: 10.1186/s40478-020-01108-z. PubMed PMID:33413694 PubMed Central PMC7791879.

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer's Disease. Frost, M, Keable, A, Baseley, D, Sealy, A, Andreea Zbarcea, D et al.. Pharmaceuticals (Basel). 2020;13 (9):. doi: 10.3390/ph13090261. PubMed PMID:32971843 PubMed Central PMC7560129.

Funding

Alzheimer’s Research UK – Co-PI “Targeting perivascular innervation and vascular tone for improved clearance of ß-amyloid from the brain“. £88,440

Strategies for improving IPAD

Noradrenergic regulation of amyloid clearance in AD

In this project we will test the extent to which noradrenergic locus coeruleus and cholinergic basal forebrain projection system degeneration contributes to the progression of Alzeimer’s disease by disrupting the clearance of amyloid-β (Aβ) peptides from the brain via the IPAD pathway.

BrightFocus Foundation (USA) collaboration with Michigan State University

Strategies for improving IPAD

Anhydrase Inhibitors to treat Alzheimer’s Disease

Here, we will test the overarching hypothesis that carbonic anhydrase inhibitors have the potential to prevent mitochondrial and cell death pathways induced by the deposition of Aβ in IPAD pathways around smooth muscle cells, preventing/delaying cerebral amyloid angiopathy.

The Edward N. and Della L. Thome Memorial Foundation collaborative project with Dr. Silvia Fossati, Unniversity of Pennsylvania

Immunisation Strategies

Investigating Immunisation Strategies for the Treatment of Synucleinopathies

Next generation immunisation strategies have enabled the manufacture of highly efficacious vaccines to treat major global diseases which are currently untreatable. United Neuroscience (UNS), a biotechnological company, has aimed to overcome the current vaccine challenges in the field of neurodegenerative disease by designing highly targeted vaccines which elicit a protective immune response. Synucleinopathies comprise a group of neurodegenerative diseases that are characterised by primary alpha-synuclein (α-Syn) pathology such as Dementia with Lewy Bodies (DLB), Parkinson’s disease (PD) and Multiple systems atrophy (MSA). The central role of α-Syn in the pathogenesis of these diseases highlights it as a promising target for therapy. In this study we aim to test the effects of novel α-Syn vaccines developed by UNS on preventing the onset and progression of neurodegeneration in mouse models of these synucleinopathies. In order to investigate this, we first need to understand the pathway along which α-Syn is naturally cleared from the brain and we can then establish how immunotherapy modulates this process and evaluate the neuroprotective effects of this as a treatment.

Key researcher

Jacqui Nimmo

PHD STUDENT

  • jtn1g13@soton.ac.uk

Output

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials. Nimmo, JT, Kelly, L, Verma, A, Carare, RO, Nicoll, JAR et al.. Front Neurosci. 2021;15 :733857. doi: 10.3389/fnins.2021.733857. PubMed PMID:34539340 PubMed Central PMC8441015.

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. Nimmo, JT, Verma, A, Dodart, JC, Wang, CY, Savistchenko, J et al.. Alzheimers Res Ther. 2020;12 (1):159. doi: 10.1186/s13195-020-00727-x. PubMed PMID:33256825 PubMed Central PMC7702704.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. Owasil, R, O'Neill, R, Keable, A, Nimmo, J, MacGregor Sharp, M et al.. Int J Mol Sci. 2020;21 (4):. doi: 10.3390/ijms21041225. PubMed PMID:32059400 PubMed Central PMC7072949.

Search PubMed

Output

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. Nimmo, JT, Verma, A, Dodart, JC, Wang, CY, Savistchenko, J et al.. Alzheimers Res Ther. 2020;12 (1):159. doi: 10.1186/s13195-020-00727-x. PubMed PMID:33256825 PubMed Central PMC7702704.

Funding

United Neuroscience project grant – “New immunisation strategies for Alzheimer’s disease“. £250,000

Medical Research Council UK & United Neurosciences  “Investigating immunisation strategies for the treatment of alpha synucleinopathies“.  £70,000